PROJECT SUMMARY Traumatic Brain Injuries (TBIs) result in a range of complex neurophysiological and functional deficits, severe long-term disability, and poor prognosis for the affected individuals. The significant brain tissue loss encountered post-TBI is a major contributor to these poor outcomes. Current interventions that target single components of TBI related trauma have largely failed to prevent widespread brain tissue loss and promote repair and functional recovery. Transplanted and host Neural Stem Cells (NSCs) possess multifaceted therapeutic potential, owing to their ability to produce efficacious amounts of neuroprotective factors in addition to facilitating complex large-scale repair and reconstruction of damaged brain tissue. However, current strategies fail to augment endogenous NSC and trophic factor activity necessary to promote long-lasting repair and recovery after a moderate-to-severe TBI. We hypothesize that the transplantation of allogeneic exogenous NSCs in a selectively engineered glycomaterial matrix capable of attracting and retaining endogenous NSCs and protective factors will facilitate functional repair of brain tissue post TBI. The creation of an ectopic NSC niche as proposed here can maintain NSCs in their undifferentiated state, and help confer neuroprotection and preservation of function chronically post-TBI. Toward this goal, we will exploit the unique structural and functional attributes of Chondroitin Sulfate Glycosaminoglycan (CS-GAG) sulfation to design novel engineered CS-GAG (eCS-GAG) matrices that are capable of enriching trophic factors, and maintaining transplanted and host NSCs in their undifferentiated state. We will implant eCS-GAG matrices either alone or in combination with NSCs in a rodent model of moderate-to-severe TBI. We will evaluate the enhanced potential of trophic factor enriching eCS-GAG matrices to promote NSC self-renewal and facilitate neuroprotection and functional recovery chronically post-TBI when compared to other sulfated and unsulfated GAG matrix controls. Our approach is novel in that it exploits the compositional and functional diversity of CS-GAG sulfation to facilitate the haptotaxis of endogenous NSCs, and presentation of endogenous protective factors within the engineered chemistry of the matrix to significantly improve NSC efficacy after moderate-to-severe TBI.